Selected amino acid changes in HIV-1 subtype-C gp41 are associated with specific gp120V3 signatures in the regulation of co-receptor usage

► We analyzed genetic signatures in V3/gp41 underlying HIV-1 clade C co-receptor usage. ► Specific V3 signatures significantly associated with CCR5 or CXCR4 usage were found. ► Specific gp41 mutations significantly associated with R5 or X4 usage were found. ► Statistically significant correlations between V3-gp41 tropic signatures were found. ► Our findings fortify prior remarks that tropic-determinants may also reside in gp41.